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Updated: Apr 26, 2026
Assessment of the Immunomodulatory Properties of Human Mesenchymal Stem Cells MSCs
Published on: December 24, 2015
A p38 MAPK-mediated alteration of COX-2/PGE2 regulates immunomodulatory properties in human mesenchymal stem cell
Kyung-Rok Yu1, Jin Young Lee1, Hyung-Sik Kim2
1Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, South Korea; Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
Abstract:
Because human mesenchymal stem cells (hMSC) have profound immunomodulatory effects, many attempts have been made to use hMSCs in preclinical and clinical trials. For hMSCs to be used in therapy, a large population of hMSCs must be generated by in vitro expansion. However, the immunomodulatory changes following the in vitro expansion of hMSCs have not been elucidated. In this study, we evaluated the effect of replicative senescence on the immunomodulatory ability of hMSCs in vitro and in vivo. Late-passage hMSCs showed impaired suppressive effect on mitogen-induced mononuclear cell proliferation. Strikingly, late-passage hMSCs had a significantly compromised protective effect against mouse experimental colitis, which was confirmed by gross and histologic examination. Among the anti-inflammatory cytokines, the production of prostaglandin E2 (PGE2) and the expression of its primary enzyme, cyclooxygenase-2 (COX-2), were profoundly increased by pre-stimulation with interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α), and this response was significantly decreased with consecutive passages. We demonstrated that the impaired phosphorylation activity of p38 MAP kinase (p38 MAPK) in late-passage hMSCs led to a compromised immunomodulatory ability through the regulation of COX-2. In conclusion, our data indicate that the immunomodulatory ability of hMSCs gradually declines with consecutive passages via a p38-mediated alteration of COX-2 and PGE2 levels.
Insights
Human mesenchymal stem cells (hMSCs) lose immunomodulatory function with expansion due to replicative senescence. This decline, mediated by p38 MAPK and COX-2, impacts their therapeutic potential.
Area of Science:
- Immunology
- Cell Biology
- Regenerative Medicine
Background:
- Human mesenchymal stem cells (hMSCs) possess significant immunomodulatory properties, making them promising for therapeutic applications.
- In vitro expansion is necessary to generate sufficient hMSC numbers for clinical use, but its effect on immunomodulation is not fully understood.
Purpose of the Study:
- To investigate the impact of replicative senescence on the immunomodulatory capacity of hMSCs.
- To elucidate the underlying molecular mechanisms responsible for changes in hMSC immunomodulation during in vitro expansion.
Main Methods:
- Evaluated the in vitro and in vivo immunomodulatory effects of late-passage hMSCs.
- Assessed the suppressive capacity on mitogen-induced mononuclear cell proliferation and protective effects in a mouse model of experimental colitis.
- Measured prostaglandin E2 (PGE2) production and cyclooxygenase-2 (COX-2) expression following stimulation with interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α).
- Investigated the role of p38 MAP kinase (p38 MAPK) phosphorylation in regulating COX-2 expression.
Main Results:
- Late-passage hMSCs exhibited diminished suppressive effects on mononuclear cell proliferation and reduced protective efficacy in experimental colitis.
- Pre-stimulation with IFN-γ and TNF-α led to increased PGE2 production and COX-2 expression in early-passage hMSCs, a response significantly reduced in late-passage cells.
- Impaired p38 MAPK phosphorylation in late-passage hMSCs was identified as a key factor in the compromised regulation of COX-2.
Conclusions:
- Replicative senescence progressively impairs the immunomodulatory ability of hMSCs.
- The decline in hMSC immunomodulation is associated with altered p38 MAPK signaling, leading to reduced COX-2 and PGE2 levels.
- These findings highlight the importance of passage number in determining the therapeutic efficacy of hMSCs.
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